Imidazoline derivatives of 2-aryl indolines



United 2,808,413 Patented Oct. 7 1

and

IMIDAZOLINE DERIVATIVES F Z-ARYL INDOLINES No Drawing. Originalapplication May'll, 1954, Serial No. 429,102, now Patent No. 2,751,393,dated June 19,

1956. Divided and Serial No. 576,513

Claims priority, application Switzerland May 13, B53 3 Claims. (Cl.260309.6)

This invention is concerned with irnidazoline derivatives of 2-arylindolines of the general formula:

wherein R represents hydrogen or a lower alkyl group, Y- represents amember selected from the group consisting of phenyl radicals substitutedat vicinal carbon atoms by a bivalent radical selected from the groupconsisting of trimethylene and tetramethylene radicals, phenyl radicalssubstituted by at most two members selected from the group consisting ofhydrogen, halogen, lower alkyl, lower alkoxy and hydroxy radicals, andnaphthyl radicals substituted by one member selected from the groupconsisting of hydrogen, halogen and lower alkyl radicals, Z1 representshydrogen, halogen, a lower alkyl or alkoxy group or a hydroxyl group andZ2 represents hydrogen, halogen or, a lower alkyl group.

' It has now been found that compounds of this type have an excellentsympathicolytic action.

The new compounds can be produced by reacting at a raised temperature acompound of the general formula:

Z err-Y NH II with a salt of a 2-halogen methyl-imidazoline of thegeneral formula: I

/NCH2 HalOHzC NH-CH2 III wherein Hal represents a halogen atom and R, Y,Z1 and Z; have themeanings given above. At about 130160, the reaction iscompleted within a few hours. It is advantageous to perform the reactionin a melt without the addition of solvents or diluents whilst ensuringthe exclusion of oxygen from the atmosphere. If desired compoundscontaining alkoxy groups can then be hydrolysed to form compoundscontaining hydroxyl groups.

A modification of the method described above which can be used, however,only for the production of derivatives containing no hydroxyl groupsconsists in converting a compound of the general formula:

wherein R, and Z2 have the meanings given above, and

this application March 20, 1956,

Y has the meaning given above for Y with the exception of hydroxylsubstituted phenyl radicals, and Z 1 has the meaning given above for Z1with the exception of the hydroxyl group, into its alkali salt by meansof a com pound giving off alkali, such as, e. g. sodium amide, potassiumamide, lithium hydride or by means of an alkali metal and then reactingthis alkali salt with a 2-halogen Inethyl-imidazoline of the generalFormula III. This reaction is performed advantageously in solvents atless high temperatures, e. g. in boiling benzene or in otherhydrocarbons of the benzene series.

The 2-aryl indolines used as starting materials can be easily obtainedfrom 2-aryl indoles for example by reduction with zinc and hydrochloricacid. The 2-aryl indoles and their substitution products necessary asstarting materials for the reduction are obtained from phenylhydrazones, which may be substituted if desired, of acetophenone,propiophenone, butyrophenone, B-acetonaphthone etc., as well as furthersubstitution products of the latter which carry in the aromatic nucleusof the ketone component and/or of the hydrazine component thesubstituents according to the definition, by heating with zinc chloride.They can also be easily obtained by heating with ether borofiuoride inan inert solvent such as toluene.

The following compounds for example can be named as substituted 2-arylindoles suitable for reduction to the corresponding Z-aryl indolines:

2- (4'-chlorophenyl) -indole 2- (4-bromophenyl) -indole 2-(4'-methyl-phenyl -indole 2- (4'-ethyl-phenyl) -indole 2-(4'-isopropyl-phenyl -indole 2- 3 methyl-4-chlorophenyl) -ind ole 2- 3'.4-dimethyl-phenyl) -indole Z-hydrindenyl- (5 -indole 2- 5.6'.7.8'-tetrahydronaphthyl- 2) l-indole Z-B-naphthyl-indole 2-2'-methoXy-pl1enyl) -indole 2- 3 '-methoxy-phenyl -indole 2-4-ethoxy-phenyl) -indole 2- (3 '-hydroxyphenyl) -indole 2-(4-hydroxyphenyl) -indole Z-phenyl-S-chlor-indole2-phenyl-6-chlor-indole 2-phenyl-5 6-dichlor-indole 2-phenyl-5-brom-indole Z-phenyl-S-methyl-indole 2-phenyl-7-methyl-indole2-phenyl-5 .6-dimethyl-indole Z-phenyl-S-methoxy-ind ole2-phenyl-6-methoxy-indole 2-phenyl-5 -hydroxy-indole 2-(4'-chlorophenyl) -5-chlor-indole 2- (4-hydroxyphenyl -5-chlor-indole 2-(4'-chlorophenyl -5-rnethyl-indole 2- (3 '-methoxy-phenyl-6-methoxy-indole 2-phenyl-3-methyl-indole 2- 8-naphthyl-3-methyl-indole2-phenyl-3-ethyl-indole 2-phenyl-3-propyl-indole2-phenyl-3-isopropyl-indole 2-chloromethyland2-bromomethyl-4.5-imidazoline can be used as second reaction component.They can be easily obtained from chloroor bromo-acetonitrile andethylene diamine.

With inorganic or organic acids such as e. g. hydrochloric acid,hydrobromic acid, sulphuric acid, phosphoric acid, ethane disulphonicacid, methane sulphonic acid, tartaric acid, acetic acid, or citricacid, the new compounds form salts some of which are easily soluble inwater.

The new compounds can be administered therapeutically, e. g. for thetreatment of disturbances of the peripheral circulation or ofhypertension, either per or par'enterally. The newcompounds can beformed into tablets either as such or in the form of their saltscombined with suitable carriers, e. g. with starch, lactose or tale. Theaqueous solutions of some of the salts have an almost neutral reaction.After being made isotonic, if necessary and after sterilisation, theycan also be administered by injection. If desired, for therapeuticalapplication the new compounds can be combined with substances having asimilar action or, for example, with substances having a blocking effecton the ganglia.

EXAMPLE 1 I-[imidazolinyl-(Z)-methyll-2-pherzyl indoline parts of2-phenyl indoline and 5 parts of 2-chloromethyl imidazolinehydrochloride are heated in an oil bath for 6 hours at 140150 innertemperature under the introduction of nitrogen. The reaction mixture isthen dissolved in hot alcohol, the alcoholic solution is poured intowater and ethered out. The aqueous phase is made alkaline and theprecipitated 1-[imidazolinyl(2)-methyl] -2-phenyl indoline isrecrystallised from ethyl acetate. M. P. 139140.

EXAMPLE 2 1 [imidazolinyl (2) methyl] 2 (3 methoxyphenyl) indoline and 1[imidazolinyl (2') methyl] -2- (3"-hydroxyphenyl -indoline 13 parts of2-(3'methoxyphenyl)-indoline and 6.5 parts of chloromethyl imidazolinehydrochloride are heated at ISO-160 for 6 hours. The melt is dissolvedhot in 60 parts by volume of alcohol, then poured into 180 parts byvolume of water and extracted with ether. The acid aqueous phase is madealkaline with concentrated caustic soda lye upon which1-[imidazolinyl-(2')-methyl] -2-(3"- methoxyphenyl)-indolineprecipitates. After filtering oil, it is recrystallized from ethylacetate. M. P. 140. The alkaline filtrate is made acid to Congo red withconcentrated hydrochloric acid andl-[imidazolinyl-(2')-methyl]-2-(3-hydroxyphenyl)-indoline isprecipitated with concentrated ammonia. It is recrystallized frommethanol. M. P. 224-225 The following compounds can be produced in ananalogous manner:

1 [imidazolinyl (2) methyl] phenyl)-indoline, M. P. 160161 1[imidazolinyl (2) methyl] phenyl)-indoline, M. P. 160

1 [imidazolinyl) (2') methyl] (4" ethyl phenyl)- indoline, M. P. 122

1 [imidazolinyl (2) methyl] (3,4" dimethylphenyl)-indoline, M. P. 142

1 [imidazolinyl (2) methyl] 2 hydrindenyl- (5")-indoline, M. P. 124

1 [imidazolinyl (2') methyl] 2 [5",6",7"',8"tetrahydronaphthyl-(2)l-indoline, M. P. 139-140" 1 [imidazolinyl (2)methyl] 2 [i naphthylindoline, M. P. 141142 1 [imodazolinyl (2) methyl]2 (4 chlorophenyl)-5-chlor-indoline, M. P. 168-169 1 [imidazolinyl (2')methyl] 2 (4" methylphenyl)-5-chlor-indoline, M. P. 166

- 2 (4" chloro- 2 (4" methyl- 1 [imidazolinyl (2) methyl] 2 phenyl 5,6-

dichlor-indoline l [imidazolinyl (2') methyl] 2 (4"chlorophenyl)-5-methyl-indoline, M. P. 179181 on decomposition 1[imidazolinyl (2) methyl] 2 (4" methylphenyl)-5-rnethyl-indoline, M. P.171-172 1 [imidazolinyl (2') methyl] 2 phenyl 5,6-

dimethyl-indoline 1 [imidazolinyl (2) methyl] 2 (3"methoxyphenyl)-6-methoxy-indoline, M. P.

1 [imidazolinyl (2) methyl] 2 )3 naphthyl 6- methoxy-indoline 1[imidazolinyl (2') methyl] 2 (4" phenyl)-6-hydroxy-indoline, M. P.218-220 1 [imidazolinyl (2) methyl] 2 phenyl 3 methylindoline, M. P. 137

1 [imidazolinyl (2) methyl] 2 phenyl 3 methyl- G-methoxy-indoline, M. P.-156 1 [imidazolinyl (2) methyl] 2 (4" phenyl) -3-methyl-indoline l[imidazolinyl (2) methyl] 2 phenyl 3 ethylindoline; and

1 [imidazolinyl (2') methyl] 2 [6" chloronaphthyl- (2") l-indoline Thepresent application is a division of U. S. patent application, Ser. No.429,102, filed May 11, 1954, now

Patent No. 2,751,393. What We claim is:

V 1. A compound corresponding to the general formula:

methylethyl- Zl CH-R Z JJH-Y N N'CH1 HPC I NH-crs,

wherein R represents a member selected from the group consisting ofhydrogen and lower alkyl radicals, Y represents a member selected fromthe group consisting of phenyl radicals substituted at vicinal carbonatoms by a bivalent radical selected from the group consisting oftrimethylene and tetramethylene radicals, phenyl radicals substituted byat most two members selected from the group consisting of hydrogen,halogen, lower alkyl, lower alkoxy and hydroxy radicals, and naphthylradicals substituted by one member selected from the group consisting ofhydrogen, halogen and lower alkyl radicals, Z1 represents a memberselected from the group consisting of hydrogen, halogen, lower alkyl,lower alkoxy and hydroxyl radicals, and Z2 represents a member selectedfrom the group consisting of hydrogen, halogen and lower alkyl radicals.

2. 1 [imidazolinyl (2') methyl] 2 (4" methylphenyl -6-methoxy-indoline.

3. 1 [imidazolinyl (2') methyl] 2 (4" methylphenyl) -5 -chlor-indoline.

References Cited in the file of this patent UNITED STATES PATENTS2,751,393 Schindler et a1. June 19, 1956

1. A COMPOUND CORRESPONDING TO THE GENERAL FORMULA: